Evaluation of Anemia

In most instances, the office presentation of anemia is incidental, with no obvious cause and no hemodynamic compromise. Because anemia is not a diagnosis, its appearance necessitates identification of the underlying cause, especially in men, women who are neither menstruating nor pregnant, and the elderly; in all these groups, the probability of disease is high. In more than 50% of cases, a clinically important cause is discovered. The task for the primary physician is to design a cost-effective assessment that concentrates on testing for causes of prognostic significance.

DEFINITION, PATHOPHYSIOLOGY, AND CLINICAL PRESENTATION (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 and 23)

Definition

Anemia is defined as a reduction in the hematocrit or hemoglobin concentration. The widely accepted World Health Organization definition is expressed in terms of hemoglobin concentration: for male adults, less than 13 g/dL; for nonpregnant women, less than 12 g/dL; and for pregnant women, less than 11 g/dL. Although the cutoff points are somewhat arbitrary, derived statistically from population data, these numbers can have meaning for individual patients because they tend to correlate with health status and prognosis, particularly in the elderly. Although the mean hemoglobin concentration tends to decline with age, the significance of anemia does not, and consequently, the diagnostic criteria are not adjusted downward for age. Because anemia is defined in terms of red cell mass and hemoglobin concentration, a spurious diagnosis of anemia may be made when the plasma volume is expanded. Similarly, if the plasma volume is contracted, a true anemia may be masked.

Pathophysiology

Anemia may result from bleeding, inadequate red cell production, or excessive red cell destruction; often, two or more mechanisms operate simultaneously. Production is decreased when defects in stem cell proliferation or differentiation, DNA synthesis, hemoglobin synthesis, or a combination of these deficiencies is present. Excessive destruction can result from membrane disorders, abnormal hemoglobins, enzyme deficiencies, and a host of extrinsic problems, such as mechanical disruption or antibodymediated injury.

The development of symptoms and signs depends on the abruptness and severity of onset, age of the patient, and ability of the cardiopulmonary system to compensate for the decrease in blood volume and oxygen-carrying capacity. When onset is gradual, symptoms may be minimal because there is adequate time for compensatory adjustments to occur. Important responses include an increase in 2,3-diphosphoglycerate, which facilitates oxygen delivery to tissues, and an expansion of the plasma volume.

Clinical Presentation

Symptoms are a function of the severity and the speed of onset of the anemia. Patients experiencing a rapid onset of anemia, with little time for the compensatory mechanisms to act, are likely to have the most symptoms. Those who have a hematocrit greater than 30% and a gradual onset and are otherwise in good health rarely note symptoms. However, if the hematocrit falls further, exertional dyspnea and fatigue may begin to appear after strenuous activity. Greater reductions in the hematocrit result in cardiopulmonary symptoms that come with less activity. Age and cardiopulmonary reserve are also important determinants of symptoms. A potpourri of nonspecific complaints frequently accompanies anemia, including headache, tinnitus, poor concentration, palpitations, vague abdominal discomfort, anorexia, nausea, and diarrhea or constipation. Tachycardia and diminished peripheral resistance occur as the hemoglobin falls to less than 7.5 g/100 mL; a systolic flow murmur resulting from high output is common. Pallor is an obvious finding, best seen in the conjunctiva, but it is of little help as an indicator of severity. More specific clinical findings depend on the underlying cause, which can best be classified on the basis of red cell morphology (determined by the appearance on a Wright-stained peripheral smear, the mean corpuscular volume [MCV] calculated by an autoanalyzer, and the degree of anisocytosis).

Microcytic Anemias

Iron Deficiency

Inadequate dietary intake, inadequate absorption, and excessive blood loss may result in iron-deficiency anemia. Most patients with mild disease are asymptomatic and manifest only a low-grade microcytic anemia. In otherwise healthy menstruating women, iron deficiency is often blamed for a host of symptoms, including fatigue, headache, paresthesias, and irritability. Although fatigue may certainly be a manifestation of severe anemia, the correlation between these symptoms and hemoglobin concentration has been poor in women with mild anemia. In placebocontrolled, double-blinded studies, they fail to show consistent symptomatic benefit with iron therapy. Some investigators attribute menorrhagia to instances of iron deficiency, but others dispute this. Pica and dysphagia (caused by an esophageal web) are classic, although rare, features today.

The physical findings that occur in the case of iron deficiency are a bit more specific. Atrophic glossitis and cheilitis are common features; koilonychia, with spooning, ridging, and thinning, is rare. Other physical findings and symptoms are manifestations of the underlying cause. The earliest laboratory changes are depletion of marrow iron stores and a corresponding fall in serum ferritin. These are followed by a decrease in serum iron and an increase in transferrin, which in many cases produce a reduction in the transferrin saturation to less than 16%. The first change in the peripheral blood is a drop in the hematocrit and hemoglobin concentration. An anisocytosis develops, manifested by an elevation in the red cell distribution width (RDW). Later, with increasing severity of anemia (hemoglobin concentration <9 g/dL), red cells become microcytic and eventually hypochromic. The degree of microcytosis is usually modest (MCV usually does not fall below 80 unless the hematocrit falls below 30 and the red cell count below 4 million).

Thalassemia Minor (Thalassemia Trait)

This condition is typically detected in asymptomatic patients undergoing an evaluation for a microcytic hypochromic anemia that does not respond to iron. A gene defect leads to impaired
red cell maturation by causing an excess of either α or β chains of hemoglobin to accumulate. The most prevalent form is β–thalassemia trait, common among persons of Mediterranean ancestry. It is associated with an increase in hemoglobin A2. There are no characteristic physical findings. The red cell count is elevated, and the smear may reveal target cells, basophilic stippling, polychromatophilia, poikilocytosis, and anisocytosis in addition to microcytosis. The MCV in thalassemia is disproportionately low compared to that in other microcytic anemias, readily falling to less than 70. The Metzger index (ratio of MCV divided by red cell count) is low in such patients. α–Thalassemia trait is seen among African Americans. The hemoglobin A2 level is normal, but a mild anemia, hypochromia, and microcytosis are present.

Anemia of Chronic Disease

Although it is usually normochromic-normocytic, this anemia can mimic that of iron deficiency in having a low serum iron and sometimes presenting as a microcytic anemia, though the degree of microcytosis is typically modest (MCV rarely <70) and the percent saturation is higher due to a reduced transferrin level (see Workup).

Sideroblastic Anemias

Sideroblastic anemias form a heterogeneous set of disorders, which include a primary type, which may be a preleukemic state; a congenital pyridoxine-responsive variant; and secondary variants associated with rheumatoid arthritis, polyarteritis, malabsorption, chronic alcoholism, cancer, porphyria, copper, zinc, or lead poisoning, and true pyridoxine deficiency. These, too, are conditions of abnormal red cell maturation. They can lead to significant anemia requiring repeated transfusion of red cells.

Their hallmark is the accumulation of nonheme iron within the mitochondria of red cells. When stained for iron, immature red cells demonstrate a ring of stain around the nucleus (ringed sideroblasts). The spleen is usually not enlarged, in contrast to myeloproliferative disorders. The smear is classically microcytic but may be normocytic, macrocytic, or dimorphic, especially in acquired forms. Cells can be hypochromic and microcytic, which lead to confusion with iron deficiency. The degree of microcytosis is usually modest and rarely below 70. Anisocytosis and poikilocytosis are pronounced. The serum iron is elevated, as is transferrin saturation. Marrow iron stains show many abnormal ringed sideroblasts. The anemia may be refractory and is sometimes associated with myelodysplasia (see later discussion), marrow failure, and transformation to acute myeloid leukemia.

Macrocytic Anemias

Vitamin B₁₂ Deficiency

Onset is typically after the age of 60 years with a prevalence of 1.9% in that age group and higher rates (4.0% to 4.3%) among those of European and African ancestry. As a consequence of the deficiency, dyssynchrony between maturation of the cytoplasm and the nucleus develops, producing the characteristic macrocytosis, immature nuclei, and hypersegmented polymorphonuclear leukocytes. Intramedullary hemolysis with LDH elevation and reduction in haptoglobin results from the ineffective erythropoiesis. Leukopenia and thrombocytopenia may appear. Sources of B₁₂ deficiency include malabsorption of B₁₂ and dietary deficiency.

Malabsorption of Vitamin B₁₂.

Absorption of B₁₂ requires acidfacilitated splitting of cobalamin from dietary protein and attachment of parietal-cell-derived intrinsic factor for uptake in the terminal ileum. Marked B₁₂ malabsorption leading to significant deficiency of the vitamin can occur as a consequence of pernicious anemia, gastrectomy, and ileal disease (e.g., Crohn disease, celiac disease, terminal ileum resection). Milder degrees of impaired B₁₂ absorption may result from atrophic gastritisinduced hypochlorhydria and from chronic use of metformin.

Pernicious Anemia.

Autoimmune gastritis with autoantibodies to parietal cells and intrinsic factor are the pathophysiologic hallmarks of pernicious anemia. Such autoantibody production may occur in isolation or in the context of other autoantibody-related diseases (e.g., Hashimoto thyroiditis, vitiligo, type 1 diabetes). Iron-deficiency anemia may also ensue from the destruction of parietal cells and often predates the onset of B₁₂ deficiency. Median age range is 70 to 80 years. A possible association with Helicobacter infection is the subject of ongoing study.

Food-Cobalamin Malabsorption.

Lesser degrees of B₁₂ malabsorption frequently develop in the elderly in the context of mild atrophic gastritis that is largely sparing of the gastric antrum. The resulting hypochlorhydria compromises the release of proteinbound cobalamin, leading to so-called food–cobalamin malabsorption. This form of B₁₂ malabsorption is believed to be responsible for much of the vitamin B₁₂ deficiency seen in the very elderly—some estimates of prevalence are as high as 20%. Plasma levels of gastrin are elevated and those of pepsinogen are low. Although Helicobacter pylori infection is often associated with such atrophic gastritis (see Chapter 68), its association with B₁₂ deficiency remains unclear. Prolonged use of proton pump inhibitors, other acid-blocking drugs, and possibly metformin can have a similarly adverse effect on B₁₂ absorption by limiting parietal gastric acid production.

Impaired Ileal Uptake.

As noted, Crohn disease, celiac disease, and previous resection of the terminal ileum can interfere with B₁₂ uptake and lead to severe deficiency. Less well-appreciated is the chronic use of metformin, which in controlled study appears to reversibly compromise uptake in the ileum.

Dietary Deficiency.

Dietary lack of B₁₂ is rare, except in those adhering to strict vegetarian or vegan diets or severely restricting their meat and dairy products intake. Vitamin B₁₂ is available in everyday foods, and body stores can hold up to a 3-year reserve.

Clinical Presentation of B₁₂ Deficiency.

Onset is gradual. In pernicious anemia, symptoms usually become evident after the sixth decade. Gastrointestinal (GI) problems such as anorexia and diarrhea may predominate. Sore tongue resulting from atrophic glossitis is a classic presentation, as is numbness and tingling in the extremities associated with peripheral neuropathy. The neurologic deficits result from defects in the maintenance of myelin integrity. Besides peripheral neuropathy, injury to the posterior columns and corticospinal tracts of the spinal cord (i.e., subacute combined degeneration) may be present, manifested by disturbances of position and vibratory sense and incoordination leading to disordered gait, with spasticity and upturned toes noted on examination. Cortical dysfunction may also ensue, with memory loss, depression, and irritability suggesting dementia. If vitamin B₁₂ deficiency is uncorrected, demyelination can progress to axonal degeneration and irreversible neuronal death. Nerve damage can occur in the absence of anemia and often precedes it.

By the time the anemia is discovered, it may be severe. Hypersegmented polymorphonuclear leukocytes are an early finding on peripheral blood smears that is specific for the megaloblastic anemias. Oval macrocytes are also characteristic, although poikilocytosis is considerable. Classically, the MCV rises to greater than 100 µm³ and the serum vitamin B₁₂ level falls to less than 100 pg/mL, but in up to one third of cases macrocytosis may be absent or the vitamin B₁₂ level may be greater than 100 pg/mL. The serum concentration of holotranscobalamin II (the vitamin B₁₂ carrier protein) begins to decline before the vitamin B₁₂ level does. Automated determination of macrocytosis may be absent if concurrent iron deficiency is present (giving a falsely normal reading for MCV—see later discussion), but
the hypersegmented polymorphonuclear leukocytes persist and the RDW is increased reflecting the dimorphic red cell picture. Achlorhydria is found on gastric stimulation testing. Serum levels of homocysteine and methylmalonic acid increase markedly in almost all cases of B₁₂ deficiency.

Folate Deficiency

Inadequate dietary intake is the usual cause of folate deficiency because body stores are limited to a 3-month reserve. Chronic alcohol abuse is the classic cause. Increased demand sometimes occurs, as in pregnancy, hemolysis, malignancy, or severe psoriasis. Decreased uptake resulting from malabsorption or drugs (e.g., phenytoin, other anticonvulsants) also can trigger the anemia. The same is true for folate antagonists such as methotrexate, trimethoprim, and triamterene. Hematologic features resemble those of vitamin B₁₂ deficiency; no neurologic deficits are present. Folate deficiency is an important cause of hyperhomocysteinemia, which is associated with an increased risk for arterial and venous thrombosis (see Chapter 31).

Liver Disease

Hepatocellular disease is responsible for a host of anemias, especially when accompanied by alcoholism and poor diet. It accounts for many cases of macrocytic anemia. Folate deficiency, marrow suppression, hypersplenism, bleeding, and bile salt alteration of the red cell membrane all contribute. The smear shows considerable poikilocytosis with spiculated red cells and some macrocytes; if folate deficiency occurs, a megaloblastic picture is superimposed.

Myelodysplasia

The myelodysplastic syndromes are an under-recognized, heterogeneous group of myeloid stem cell disorders that have recently been classified as hematologic malignancies due to the clonal nature of the underlying pathologic process. Incidence is estimated to be as high as 10,000 new cases annually in the United States and 75 cases per 100,000 in persons over the age of 65 years, being a disease mostly of the elderly. It accounts for about a third of the anemias of unknown etiology in the elderly. Both primary and secondary forms of the disease have been identified; those which are a consequence of occupational exposure (e.g., benzene-containing solvents, pesticides) and cancer therapy (both radiation and chemotherapy) tend to have an especially poor prognosis and a high probability of transforming into acute myeloid leukemia. The inherited forms of the disease appear to be more indolent. Overall, 5-year survival is about 30%, with major differences between the inherited and acquired forms of the disease. A sideroblastic variant accounts for about 25% of patients with primary or inherited myelodysplasia, many harboring a particular gene mutation (e.g., SF3B1).

Clinical Presentation and Course.

The presenting manifestations are nonspecific, dominated by the consequences of the cytopenia, be it anemia (fatigue, exercise intolerance), neutropenia (infection), or thrombocytopenia (bleeding). The reticulocyte count is reduced and the MCV is typically increased. The anemia is usually moderate or severe (<10.0 g/dL, with 25% having severe anemia); about 40% present with concurrent neutropenia (neutrophil count <1,500 cells/µL) or thrombocytopenia (platelet count <100,000).

Prognosis can be estimated, based on the number of cytopenias, bone marrow blast percentage, and cytogenetic changes. In low–risk disease (e.g., refractory anemia), cytopenias are the major problem; in high-risk disease (e.g., refractory anemia with excess blasts) a high rate of transformation to acute myeloid leukemia complicates the picture. Treatments are emerging that can reduce the risks associated with cytopenias.

Myxedema

See discussion under Normocytic Anemias.

Normochromic-Normocytic Anemias

Anemia of Chronic Disease

A common accompaniment of chronic inflammatory diseases, malignancy, and renal failure, the anemia of chronic disease involves the trapping of iron by activated macrophages of the reticuloendothelial system, rendering it unavailable for erythropoiesis. Hepcidin, a recently discovered acute-phase protein, is believed to play a role in diverting iron to macrophages. In addition, some suppression of erythropoiesis by humoral substances (interleukins, tumor necrosis factor, prostaglandins) elaborated in the course of the underlying chronic disease process often occurs. Of interest, erythropoietin is inappropriately low in almost all cases.

The anemia is usually moderate, with hemoglobin levels in the range of 7 to 11 g/dL. Both serum iron and iron-binding capacity are reduced. The smear is most often normocytic, but it can be hypochromic and even modestly microcytic, mimicking iron deficiency. The serum iron falls before anemia sets in; transferrin saturation may be less than 16%, again simulating iron deficiency. However, marrow iron stores are normal or increased, and serum ferritin levels are usually elevated due to increased uptake and deposition of iron into the reticuloendothelial system. The reticulocyte count is low, indicating the underproduction of red cells. The degree of microcytosis is usually modest (MCV rarely <70).

Another important anemia of chronic disease is that associated with HIV infection, which affects the bone marrow. Myelofibrosis occurs. Anemia is seen in about 15% of asymptomatic HIV-positive persons, 45% of those with AIDS-related complex, and 75% of those with untreated AIDS. For unknown reasons, erythropoietin is inappropriately low. The smear in most cases is normochromic-normocytic. Rouleaux formation resulting from circulating immune complexes sometimes develops, but hemolysis is uncommon. The anemia can be exacerbated by medications used in the treatment of HIV infection (zidovudine, pentamidine, trimethoprim, sulfonamides). Zidovudine is especially toxic to marrow, causing anemia in about 30% of instances. Neutropenia and thrombocytopenia occur to a lesser extent. Patients most susceptible to the adverse hematologic effects of zidovudine are those with a low CD4 cell count, preexisting anemia, concurrent vitamin B₁₂ deficiency, or neutropenia.

Hemolytic Anemias

Hemolytic anemias constitute a diverse group. Inherited forms are caused by intrinsic red cell defects; acquired types depend primarily on extrinsic mechanisms, such as immunologic or mechanical injury. Clinical presentations vary according to the rate of destruction, compensatory adaptations, and underlying cause. Jaundice sets in when the capacity of the liver to conjugate excess bilirubin from hemoglobin breakdown is exceeded; the serum level of unconjugated bilirubin climbs. Splenomegaly evolves as the trapping of damaged red cells progresses. Sudden fever, chills, headache, back and abdominal pain, and hemoglobinuria characterize severe acute hemolysis.

The reticulocyte count is elevated unless an accompanying marrow defect is present. The peripheral smear usually appears normochromic-normocytic but may be macrocytic because of the release of immature forms during rapid red cell destruction and regeneration. Polychromatophilia is common, and nucleated red cells, stippling, schistocytes, and Howell-Jolly bodies may be noted. Spherocytes occur in hereditary spherocytosis, a condition of reduced cell membrane area resulting from a defect in the synthesis of the membrane protein spectrin. Spherocytosis is also seen in immune hemolytic anemia as a consequence of membrane loss.

Sickle Cell Disease.

Sickle cell disease is the most prevalent hemolytic condition in the African American population. Sickle cell trait is asymptomatic and anemia is absent, although mild hematuria caused by sickling in the hypertonic renal medulla sometimes occurs. The peripheral smear is normal except for an occasional target cell. Hemoglobin electrophoresis reveals less than 50% of total hemoglobin to be of the S variety. Patients homozygous for the sickle cell gene have sickle cell anemia, a much more serious condition in which painful crises are precipitated by stress (especially infection). Intravascular sickling ensues, the red cells become rigid, and vascular occlusion may result, leading to arterial desaturation, hemolysis, and organ damage. Leg ulcers, hepatomegaly, hematuria, renal concentrating defects, and mild jaundice commonly occur. Patients report acute, severe pain in the lower extremities, back, or abdomen. Fever and leukocytosis may also be present. Attacks typically last from a few hours to a few days and then resolve spontaneously. Aplastic crises develop when a concurrent illness suppresses erythropoiesis. The smear is normochromic; sickled cells may be noted in addition to target forms. Hemoglobin electrophoresis reveals a predominance of hemoglobin S. The addition of a reducing agent, such as metabisulfite, to a drop of blood causes the cells to sickle within a few minutes and confirms the diagnosis.

Glucose-6-Phosphate Dehydrogenase Deficiency.

Glucose-6-phosphate dehydrogenase deficiency is a sex-linked red cell defect compromising the enzyme that maintains hemoglobin in an unoxidized state. In its episodic form, which is seen in African Americans, the condition causes hemolysis after exposure to oxidant compounds (sulfonamides, antimalarials) or infection. A chronic variety occurs in persons of Mediterranean ancestry.

Drug-Induced Hemolytic Anemias.

Drug-induced hemolytic anemias usually manifest an immune mechanism, such as adsorption to the red cell of drug-antibody complexes (quinidine); adsorption to the red cell of drug to form a hapten, followed by the binding of antidrug antibody (high-dose penicillin); or induction of a red cell “autoantibody” (long-term methyldopa). The hallmark of most drug-related hemolytic episodes is a positive direct Coombs’ test result. Withdrawal of the offending agent ends the process.

Autoimmune Hemolytic Anemias.

Autoimmune hemolytic anemias result when patients produce antibodies against their own red cells. They are classified according to the type of antibody produced (immunoglobulin G [IgG] or immunoglobulin M [IgM]). Those of the IgG class are directed against the Rh antigen. Most are “warm” autoantibodies, although many are idiopathic; about 50% occur in the context of lymphoma, lupus, ulcerative colitis, or chronic lymphocytic leukemia. The diagnosis is made by detecting IgG and C3d proteins on the red cell surface. Macrophages that can detect these proteins bind the involved red cells. Hemolysis is mostly extravascular. The red cells are cleared by the spleen. The IgM form of autoimmune hemolytic anemia is a cold hemagglutinin condition. These antibodies are seen in mycoplasmal, Epstein-Barr virus, or cytomegalovirus infection and in lymphoproliferative conditions. Cold agglutinin titers are markedly elevated in the setting of hemolysis (>1:1,000).

Aplastic Anemias

Aplastic anemias are usually idiopathic but may be linked to a marrow toxin (cytotoxic drugs, radiation), an idiosyncratic drug reaction (chloramphenicol, gold, sulfur compounds, carbamazepine), or a viral infection (hepatitis B virus, hepatitis C virus, cytomegalovirus, HIV, parvovirus). Onset is gradual, with fatigue and bleeding noted first; infection is a later problem. No organomegaly occurs. The smear appears normochromic-normocytic, but the number of platelets is diminished. There are no signs of increased red cell production. The reticulocyte count is zero, and pancytopenia is present.

Renal Failure

The anemia of chronic renal failure is caused by a reduction in both production and survival of red cells. Lack of erythropoietin, and metabolic injury to erythrocytes are postulated mechanisms. The severity of the anemia parallels the degree of azotemia. The smear is normochromic-normocytic; burr cells are sometimes prominent. Anemia is common once the glomerular filtration rate falls to less than 60mL/min.

Hypothyroidism

Hypothyroidism is associated with a number of anemic states. The most common is a mild normochromic-normocytic anemia. Iron deficiency may occur secondary to heavy menstrual bleeding. In addition, a macrocytic picture that clears after the administration of exogenous thyroid hormone is sometimes encountered. A true megaloblastic anemia caused by vitamin B₁₂ deficiency occurs in about 10% of hypothyroid patients with a macrocytic smear; the relation between hypothyroidism and pernicious anemia is unresolved, but an autoimmune mechanism is postulated.

Only gold members can continue reading. Log In or Register to continue